Imidazole derivatives and salts thereof

ABSTRACT

1-Substituted-imidazoles of the formula: ##STR1## in which A is selected from the group consisting of straight or branched, saturated or unsaturated, acyclic hydrocarbon radicals of from 1 to 3 carbon atoms and R is ##STR2## wherein n is an integer which is at least 1, and the or each Q substituent, which when n is greater than 1 may be the same or different, is selected from a saturated alkyl group of from 1 to 4 carbon atoms or an unsaturated alkyl group of from 2 to 4 carbon atoms, with the proviso that when A is unsaturated Q may also be selected from alkoxy of from 1 to 4 carbon atoms; halo; trihalomethyl; hydroxy; carboxyl; a salt of such a carboxyl group; carboalkyloxy; carboaryloxy; carboarylalkyloxy; --NR 6  R 7  or --CONR 6  R 7  ; in which R 6  and R 7  may be the same or different and are hydrogen or alkyl of from 1 to 4 carbon atoms; the 1-substituted-imidazole being the free base or an acid addition salt thereof. 
     Methods of preparing the 1-substituted-imidazoles are also provided. 
     The imidazoles have pharmacological properties that make them of use in the treatment of thromboembolic disorders, shock and angina pectoris.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a continuation-in-part of my Application Ser. No.952 796, filed Oct. 19, 1978, now abandoned, which is in turn acontinuation-in-part of my Application Ser. No. 936 407, filed Aug. 24,1978, now abandoned.

The present invention relates to imidazole derivatives and saltsthereof, to their synthesis and intermediates therefor, topharmaceutical formulations containing such compounds and to the use ofthese compounds in medicine.

Thromboxane A₂ (TXA₂), a potent stimulator of blood plateletaggregation, is produced, in platelets, from the prostaglandinendoperoxides PGG₂ and PGH₂. Prostacyclin (PGI₂), which has potentanti-aggregatory activity, is also produced (in blood vessel walls) fromPGG₂ and PGH₂, and it has been suggested that a balance between theproduction of TXA₂ and PGI₂ is the controlling factor in thrombusformation. It would, in consequence, be desirable in the treatment andprophylaxis of thrombo-embolic disorders to be able to selectivelyinhibit TXA₂ synthetase, and thereby favour the production of theanti-aggregatory agent PGI₂.

Imidazole and 1-methylimidazole are known to provide some degree ofinhibition of the enzymic conversion of the endoperoxides (PGG₂ andPGH₂) to thromboxane A₂ by platelet microsomes (Moncada et al.,Prostaglandins, 13/4, 611-618, 1977). Certain 1-n-alkylimidazoles,especially 1-n-dodecylimidazole and its higher homologues have beendescribed as being capable of lowering serum cholesterol levels (U.K.Patent No. 1 364 312; Biochem. Pharmacol. 24, 1902-1903, 1975).

We have now discovered that TXA₂ synthetase may be inhibited by1-substituted-imidazoles, e.g. 1-arylalkylimidazoles of formula (I) andacid addition salts thereof. Compounds of formula (I) and their saltsare hereinafter referred to as the "active compounds".

The compounds of formula (I) are novel and of formula: ##STR3## in which

A is selected from the group consisting of straight or branched,saturated acyclic hydrocarbon radicals of 1, 2 or 3 carbon atoms, andstraight or branched, unsaturated acyclic hydrocarbon radicals of 2 or 3carbon atoms, and

R is ##STR4## wherein n is an integer which is at least 1, and

the or each Q substituent, which when n is greater than 1 may be thesame or different, is a saturated hydrocarbon group of from 1 to 4carbon atoms or an unsaturated hydrocarbon group of from 2 to 4 carbonatoms, with the provisos that

(a) when A is a methylene or ethylidene group, n is at least 2 when eachQ is a saturated hydrocarbon group;

(b) when A is a branched propylene, or straight propylidene group, n isat least 3 when each Q is a saturated hydrocarbon group; and

(c) when the group A is unsaturated Q may also be selected from alkoxyof from 1 to 4 carbon atoms; alkylenedioxy of from 1 to 4 carbon atomswhen n is at least 2; halo; trihalomethyl; hydroxy; carboxyl; a salt ofsuch a carboxyl group; carboalkoxy; carboaryloxy; carboarylalkyloxy;--NR⁶ R⁷ or --CONR⁶ R⁷, in which R⁶ and R⁷ may be the same or differentand are hydrogen or alkyl of from 1 to 4 carbon atoms, with the furtherproviso that when n is 1, Q is not a saturated hydrocarbon groups;

the substituted-imidazole being the free base or an acid addition saltthereof.

In formula (I) examples of the group A are:

methylene,

propylene, and,

in the orientation of formula (I), --CH₂ --CH═CH-- (cis or trans orcis-trans isomeric mixture).

A valuable class of compounds of formula (I) are those in which thearomatic ring is substituted by at least two groups Q, preferablysaturated or unsaturated hydrocarbon groups, e.g. alkyl or alkenylgroups, especially if one substituent is in the 4-position in thebenzene ring and A is either methylene (--CH₂ --), or, in theorientation of formula (I), --CH₂ --CH═CH (cis or trans- or cis-transmixture-cinnamyl compound). When A is unsaturated, preferred compoundsare those in which the aromatic ring contains alkyl, chloro or methoxysubstituents.

Compounds of formula (I) may also be used as acid addition saltsthereof, especially as pharmaceutically acceptable ones.

Especially preferred 1-arylalkyl compounds include:

1-(3,4-dimethylbenzyl)imidazole;

1-(2,4-dichlorocinnamyl)imidazole i.e.1-(3-(2,4-dichlorophenyl)prop-2-enyl)imidazole;

1-(3-(2,6-dichlorophenyl)prop-2-enyl)imidazole;

1-(2,4,6-trimethylbenzyl)imidazole; and acid addition salts thereof.

Other preferred compounds include:

1-(3-(3,4,5-trimethoxyphenyl)prop-2-enyl)imidazole;

1-(3-(3,4-dimethoxyphenyl)prop-2-enyl)imidazole;

1-(3(2-hydroxyphenyl)prop-2-enyl)imidazole;

1-(3-(3-bromophenyl)prop-2-enyl)imidazole;

1-(3-(4-chlorophenyl)prop-2-enyl)imidazole;

1-(3-(3,4-dimethylphenyl)prop-2-enyl)imidazole;

1-(3-(2-methoxyphenyl)prop-2-enyl)imidazole; and acid addition saltsthereof.

In contrast to imidazole and 1-methyl-imidazole the compounds of formula(I) are more potent inhibitors of TXA₂ synthetase. Many of the compounds(for example in (I) when A is --CH₂ -- or, in the orientation of formula(I), --CH₂ --CH═CH--) are also more selective in their action in notinhibiting other anti-aggregatory-prostaglandin generating enzymes. Thecompounds of formula (I) also do not produce the side-effects found withimidazole upon in vivo administration. The compounds of formula (I) arefurther capable of inhibiting platelet aggregation in vivo and also arecapable of disaggregating platelet clumps, e.g. the compound1-(3,4-dimethylbenzyl)imidazole and its salts especially displayingthese properties.

The compounds of formula (I) are suitable for use in the treatment orprophylaxis of angina pectoris. In some cases it is possible to preventthe onset of agina pectoris, for example when a patient with coronaryartery disease is given cardiac pacing, which leads generally to anincrease of TXA₂ in the blood, and which is associated with the onset ofangina pectoris. Also, inhibition of TXA₂ formation prevents or delaysthe onset of shock, e.g. experimentally induced shock in laboratoryanimals.

Imidazoles of formula (I) and acid addition salts thereof may be made byany method known in the art for the synthesis of compounds of analogousstructure. In general these methods comprise linking the imidazole ringto the remainder of the molecule; converting a precursor molecule byelimination of a functional group from the imidazole ring; and formationof the desired compound from a corresponding pyrazole, imidazoline, orother unsaturated analogue.

A most convenient method of synthesis involves the reaction of imidazole(formula II) or a salt thereof with an alkylating or alkenylating agentof formula (III): ##STR5## wherein R and A are as defined in formula (I)and Z is a leaving group. This reaction is well established in theliterature, and the leaving group may be chosen from a variety ofsubstituents but especially halo, preferably chloro or bromo, or fromp-toluenesulphonyloxy but other arylsulphonyloxy, alkanesulphonyloxy oraralkylsulphonyloxy radicals may be used. The reaction is preferablyperformed in the presence of an acid acceptor, for example an alkalimetal alkoxide such as sodium methoxide or potassium tertiary butoxidein the presence of an alkanol. The leaving group Z may itself be formedin situ from the corresponding alkanol (Z═OH) by reaction with ahydrohalogenic acid (e.g. hydrochloric acid or a Lewis acid, such asaluminium chloride: see Japanese Patent Kokai No. 131577/77) and theresulting agent of formula (III) reacted directly with imidazole withoutprior isolation. Alternatively an alkanol (Z═OH) or a derivative thereof(e.g. Z═R--A--O) may be reacted directly with imidazole (II) by heatingin the presence of a dehydrating agent such as phosphoric acid, or aphosphate (see Japanese Patent Publication No. 51 105 060), sulphuricacid or sulphates (see Japanese Patent Publication No. 51 105 061).

Among precursor molecules which may be converted to a compound offormula (I) or an acid addition salt thereof, are substituted imidazolederivatives of formula (IV), or acid addition salts thereof ##STR6##wherein A, n and Q are as defined in formula (I) and Q¹, Q², Q³ and Q⁴are the same or different, at least one being a radical capable ofremoval by, for example, reduction or oxidation, the remaining radicalor radicals being selected from hydrogen or a radical capable of removalin the same or another manner as the removable radical (e.g. a carboxylgroup--see formula (VI)--removed by decarboxylation), y is 0 or aninteger, with the proviso that y and n together do not exceed 5. Q¹, Q²,Q³ and Q⁴ may be selected for example from thio (--SH), alkylthio(S-alkyl, wherein alkyl has from 1 to 4 carbon atoms) or halo,preferably chloro or bromo. The reaction conditions are chosen accordingto the nature of the radicals Q¹, Q², Q³ and Q⁴. Desulphurisation may beperformed by oxidative or reductive procedures using for example nitricacid or Raney nickel; and reductive dehalogenation by the use of zincand acetic acid or Raney nickel or other reagents known in the art ordescribed in the literature.

Another class of examples include carboxyimidazoles or derivativesthereof of formula (VI): ##STR7## wherein A, n, Q, y and R are asdefined in formula (IV), at least one of R¹, R², R⁴ and R⁸ is carboxylor a derivative thereof (for example an ester such as an alkyl ester, anacid halide such as the chloride, or the nitrile) and the other is, orothers are independently, hydrogen or carboxyl or a derivative asdescribed. The compounds of formula (VI) may be converted into theimidazoles of formula (I) by any suitable decarboxylation conditionswhich may simply comprise heating the compounds with or without acatalyst such as copper.

The imidazoles of formula (I) may also be made from a compound offormula (VII): ##STR8##

wherein ##STR9## is 1-imidazoline, 1-imidazole or 1-pyrazole, A¹ is astraight or branched saturated or unsaturated acyclic hydrocarbonradical which may include a keto group, and R³ is ##STR10## as definedin formula (I), or when A is unsaturated Q may be nitro, provided thatat least one of ##STR11## A¹ and R³ is other than 1-imidazole, asaturated acyclic hydrocarbon and ##STR12## respectively as defined informula (I). Thus an imidazoline (VIII): ##STR13##

wherein one of represents an extra bond and, A and R are as defined informula (I) may be dehydrogenated to the corresponding imidazole in thepresence of a catalyst, for example by heating to 250° C. in thepresence of palladium, nickel or platinum under pressure, or by heatingwith a dehydrogenating agent, such as selenium or copper oxide.1-Pyrazole compounds (VII) may be treated with ultra-violet radiation,optionally under an inert atmosphere (e.g. argon) in for example1,2-dimethoxyethane at room or elevated temperatures (see for example"Ring Transformations of Heterocycles" edited van der Plas, AcademicPress, 1973 at page 261). The unsaturated imidazoles of formula (I) (informula (VII), A¹ and/or Q (within R³) are unsaturated) may be reducedto the corresponding less saturated or completely saturated compounds(but not reducing any aromatic nucleus) e.g. by hydrogenation with anoble metal catalyst, for example platinum or palladium in an alkanol.If Q is amino in the final product then its precursor may be anitrogen-containing group reducible to amino, e.g. nitro. A compound offor example formula (IX); ##STR14##

where R is as defined in formula (I), may be reduced at the keto groupto a --CH₂ -- group for example by a Clemmensen reduction.

When one or more of the Q groups is an alkyl or alkenyl group it may beintroduced into the phenyl ring by a Friedel Crafts or similarLewis-acid catalysed reaction of the type ##STR15##

wherein A, Q and n are as defined for formula (I), x is an integer lessthan or equal to n and Z¹ is a leaving group, e.g. halo, suitable foruse in this type of reaction.

Compounds of formula (I) may also be prepared by cyclising, preferablyin the presence of an acid acceptor, a compound of formula (XI);##STR16##

wherein A, R and n are as defined for formula (I) and X² is a leavinggroup.

Compounds of formula (I) may also be prepared by reacting a compound offormula (XII); ##STR17##

wherein A, R and n are as defined for formula (I) with a compound offormula (XIII); ##STR18##

wherein either of X³ and Y³ is a leaving group such as halo or hydroxyand the other is hydrogen or X³ and Y³ are both halo or together withthe carbon atom to which they are attached form an aldehyde group or anacetal derivative thereof e.g. both X³ and Y³ are alkoxy, and X⁴ and Y⁴are as defined for X³ and Y³, although they may be the same as ordifferent from X³ and Y³.

An imine salt of for example formula (XIIIa); ##STR19##

(wherein R is as defined for formula (I), X⁻ is an anion, A² is achemical bond or a straight or branching, saturated or unsaturatedacyclic hydrocarbon radical, which may include a keto group, A³ ishydrogen or a saturated or unsaturated acyclic hydrocarbon radical,which may include a keto group, with the proviso that A² and A³ togethercontain no more than 2 carbon atoms), may be reduced to thecorresponding compound of formula (I) by e.g. zinc and a mineral acid,e.g. hydrochloric acid.

The intermediates for use in the above-described reactions may also bemade by conventional methods known in the art. Thus the 1-pyrazole and1-imidazoline intermediates (formula (VII)) may be prepared byalkylation of pyrazole and imidazoline in an analogous manner to thatdescribed above for preparation of the corresponding imidazoles. Theintermediates of formula (III) may be made in known manner preferably byhalogenation of the corresponding alcohols (formula (III), Z=--OH). WhenA is unsaturated with three carbon atoms, the alcohol may be preparedfrom paraformaldehyde and the corresponding unsaturated A compound withtwo carbon atoms by analogy with the method described in Bull, Chem.Soc., Japan, 46/48, 25/2-5, (1973). The substituted imidazoleintermediates of formula (IV) may be made in known manner, for examplesee "Imidazole and its derivatives" Part 1, Ed. K. Hoffmann,Interscience Publishers Inc. New York, 1973. For example the2-thioimidazoles of formula (IV) may be made by cyclisation of an acetalof formula (XIV): ##STR20## with thiocyanate, wherein R⁵ is alkyl, arylor arylalkyl.

The pharmaceutically acceptable acid addition salts of the compounds offormula (I) may be prepared by any method known in the art. Inparticular they may be prepared by treating the parent imidazole withthe appropriate acid.

Examples of the acid addition salts of the compounds of formula (I)include those salts derived from the following acids: oxalic,hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicyclic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic,benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic.

The imidazoles of formula (I) may be used in conjunction with aphosphodiesterase inhibitor, which provides a further, synergistic,increase in effect, as it acts against platelet aggregation by adifferent pathway.

Suitable (cyclic AMP) phosphodiesterase inhibitors for use inpotentiating the anti-aggregatory effects of the active compoundsinclude as such or as pharmaceutically acceptable salts:

(a) Xanthine derivatives such as:

Theophylline(3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), and saltsthereof;

3-Isobutyl-1-methyl-xanthine;

Caffeine(3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione) and saltsthereof; and

Aminophylline (adduct of Theophylline and 1,2-ethanediamine (2:1)).

(b) Isoquinoline derivatives, for example:

Papaverine(1-(3,4-dimethoxyhenyl)methyl-6,7-dimethoxyisoquinoline) andsalts thereof; and

6,7-Diethoxy-1-(4,5-diethoxybenzyl)isoquinoline or its salts e.g. itshydrochloride;

(c) Derivatives of pyrimido(5,4-d)pyrimidine, for example:

Dipyridamole(2,2',2",2'"-(4,8-dipiperidinopyrimido[5,4-d]pyrimidin-2,6-diyldinitrilo)-tetraethanol)and its salts;

2,2',2",2'"-[[4-(1-piperidinyl)pyrimido[5,4-d]pyrimidin-2,6-diyl]dinitrilo]tetrakisethanoland its salts; and

2,4,6-tri-4-morpholinylpyrimido[5,4-d]pyrimidine and its salts.

(d) Derivatives of thieno[3,2-d]pyrimidine, for example:

N-[4-(4-morpholinyl)thieno[3,2-d]pyrimidin-2-yl]-1,2-ethanediamine.

(e) Derivatives ofpyrazolo[3',4':2,3]pyrido[4,5-b][1,5]benzodiazepin-6-(3H)-one, forexample:

3-Ethyl-7,12-dihydro-7,12-dimethylpyrazolo[4',3':5,6]pyrido[4,3-b]-[1,5]benzodiazepin-6-(3H)-one;

3-Ethyl-7,12-dihydro-9-methoxy-7,12-dimethylpyrazolo[3',4':2,3]pyrido[4,5-b][1,5]-benzodiazepin-6-(3H)-one;and

10-Chloro-3-ethyl-7,12-dimethyl-7,12-dihydropyrazolo[4',3':5,6]pyrido[4,3-b][1,5]benzodiazepin-6-(3H)-one.

(f) Derivatives of 1H- or 2H-pyrazolo[3,4-b]pyridine, for example:

4-(Butylamino)-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acidethyl ester;

4-(Butylamino)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester;

4-Chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-acetonitrile;

1-Ethyl-4-(isopropylidenehydrazino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid ethyl ester or its salt such as its hydrochloride hemihydrate; and

2-Methyl-6-phenyl-4-(1-piperidinyl)-2H-pyrazolo[3,4-b]pyridine or itssalts e.g. its hydrochloride.

(g) Derivatives of 5H-furo-[3,4-e]pyrazolo[3,4-b]pyridine-5-one, forexample:

4-(Butylamino)-1-ethyl-1,7-dihydro-7-hydroxy-5H-furo-[3,4-e]pyrazolo[3,4-b]pyridine-5-one;and

(h) Derivatives of 1(2H)-naphthalenone, for example:

2[(Dimethylamino)methyl]-3,4-dihydro-7-methoxy-1(2H)-naphthalenone orits salts e.g. its 1:1 hydrochloride.

The active compounds are particularly useful in the treatment and/orprophylaxis of thrombo-embolic disorders in mammals, including man. Itis to be understood that the term "thrombo-embolic disorder" includesthose disorders whose etiology is associated with platelet aggregation.

The active compounds are useful wherever it is desired to inhibitplatelet aggregation and/or to reduce the adhesive character ofplatelets, and consequently to treat or prevent the formation of thrombiin mammals, including man. For example, the compounds are useful in thetreatment and prevention of myocardial infarcts, cerebro-vascularthrombosis and ischaemic peripheral vascular disease; to treat andprevent post-operative thrombosis; and to promote patency of vasculargrafts following surgery.

The active compounds are also useful as an addition to blood, bloodproducts, blood substitutes and other fluids which are used inartificial extracorporeal circulation and perfusion of isolated bodyportions, e.g., limbs and organs, whether attached to the original body,detached and being preserved or prepared for transplant, or attached toa new body. It may also be used in laboratory animals, e.g. cats, dogs,rabbits, monkeys and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

The active compounds also exhibit some vasodilatory action on bloodvessels and therefore have a utility as anti-hypertensives for thetreatment of high blood pressure in mammals, including man.

The active compounds may also be used in the preventing, treatment orprophylaxis of angina pectoris and in the prevention or delay of theonset of shock.

The amount of active compound required for therapeutic or prophylacticeffect will vary with the route of administration, and the nature of thecondition under treatment. In general a suitable dose for a mammal,including man, of active compound will lie in the range of 0.1 to 300 mgper kg body weight, particularly from 0.5 to 10 mg per kg body weight,for example 2 mg per kg. A suitable single oral dose for an adult humanlies within the range of 50 to 600 mg, for example 150 mg, given saythree times a day.

While it is possible for an active compound to be administered as theraw chemical it is preferable to present it as a pharmaceuticalformulation. The formulations, both for veterinary and for human medicaluse, of the present invention comprise an active compound as abovedefined, together with one or more acceptable carriers therefor andoptionally other therapeutic ingredients. The carrier(s) must be`acceptable` in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Unitdoses of a formulation may contain between 60 mg and 1.5 g of an activecompound.

The formulations include those suitable for oral, rectal, vaginal orparenteral (including subcutaneous, intramuscular and intravenous)administration. Preferred formulations include tablets, capsules andinjectable suspensions or solutions.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing into association the activecompound (in the form of the base or a pharmaceutically acceptable acidaddition salt) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active compound with liquidcarrier(s) or finely divided solid carrier(s) or both, and then, ifnecessary, shaping the product into the desired formulation.

It will be appreciated from the foregoing that the present inventionprovides the following features:-

(a) Novel 1-substituted imidazoles of formula (I) and acid additionsalts thereof.

(b) Methods of preparing imidazoles of formula (I) and acid additionsalts thereof.

(c) Pharmaceutical formulations containing an imidazole of formula (I)or a pharmaceutically acceptable acid addition salt thereof and apharmaceutically acceptable carrier.

(d) Method of preparing the pharmaceutical formulations containing animidazole of formula (I) or a pharmaceutically acceptable acid additionsalt thereof.

(e) A method for the treatment or prophylaxis of a thrombo-embolicdisorder in a mammal or mammalian tissue, including man or human tissue,comprising administering an effective amount of an active compound.

(f) A method of prevention, treatment or prophylaxis of angina pectorisin a mammal, including man, which comprises administering to the mammal,an effective amount of an imidazole of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof.

(g) A method of preventing or delaying the onset of shock in a mammalwhich comprises administering to the mammal an effective amount of animidazole of formula (I) or a pharmaceutically acceptable acid additionsalt thereof.

The following Examples are provided by way of an illustration of thepresent invention and should in no way be construed as constituting alimitation thereof. All temperatures are given in degrees Celsius.

EXAMPLE 1 Preparation of 1-(3,4-Dimethylbenzyl)imidazole

1-Chloromethyl-3,4-dimethylbenzene (34.76 g, 0.225 mol) was added to amixture of imidazole (13.6 g, 0.2 mol) and sodium bicarbonate (16.8 g,0.2 mol) in dry methanol (100 ml). Following the addition, the reactionmixture was stirred and heated under reflux for 3 hours (h).

After cooling, the reactor mixture was filtered, and the filtrate wasevaporated under reduced pressure to afford a yellow oil. The residuewas extracted with chloroform (3×100 ml), and the combined extracts werewashed with saturated brine (100 ml). The chloroform solution was driedover magnesium sulphate, and then concentrated under reduced pressure.The resulting oil was purified using a silica gel column and ethylacetate/methanol (9:1) as eluent. The product fractions were pooled,concentrated, and the resulting oil was distilled to afford1-(3,4-dimethylbenzyl)imidazole, b.p. 128°-130°/0.3 mm Hg.

EXAMPLE 2 Salts of 1-(3,4-Dimethylbenzyl)imidazole A. Hydrogen Fumarate

A solution of fumaric acid (0.29 g, 0.0025 mol) in hot ethanol (10 ml)was added to a stirred solution of 1-(3,4-dimethylbenzyl)imidazole (0.46g, 0.0025 mol) in hot ethanol (10 ml). After boiling for 0.25 h, thesolution was evaporated to afford a white solid. Recrystallisation ofthe solid from ethyl acetate afforded 1-(3,4-dimethylbenzyl)imidazolehydrogen fumarate 1/6 hydrate as a white solid m.p. 138°-140°.

B. Hydrogen Succinate

A hot solution of succinic acid (0.295 g, 0.0025 mol) in ethanol (20 ml)was added to a stirred, hot solution of 1-(3,4-dimethylbenzyl)imidazole(0.46 g, 0.0025 mol) in hot ethanol (10 ml). After boiling for 0.25 h,the solution was evaporated under reduced pressure to afford a whitesolid. Recrystallisation of the solid from ethyl acetate/petroleum ether(b.p. 40°-60°) afforded 1-(3,4-dimethylbenzyl)imidazole hydrogensuccinate as white crystals, m.p. 134°-135°

C. Hydrogen Oxalate

A hot solution of oxalic acid (0.225 g, 0.0025 mol) in dry ethanol (10ml) was added to a solution of 1-(3,4-dimethylbenzyl)imidazole (0.46 g,0.0025 mol) in hot ethanol (20 ml). After boiling for 0.25 h, thesolution was evaporated to afford a white solid. Recrystallisation ofthe solid from ethanol/petroleum ether (b.p. 40°-60°) afforded1-(3,4-dimethylbenzyl)imidazole hydrogen oxalate as a white solid, m.p.92°-93°.

EXAMPLE 3 Preparation of 1-[3-(2,4-Dichlorophenyl)prop-2-enyl]imidazole

1-Chloro-3-(2,4-dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was addeddropwise to a stirrer solution of imidazole (3.4 g, 0.05 mol) andpotassium tert-butoxide (5.6 g, 0.05 mol) in butan-1-ol (100 ml).Following the addition, the reaction mixture was stirred and heatedunder reflux for 3.5 h.

After cooling, the reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. Hydrochloric acid (150 ml, 2 M) wasthen added to the residue and the aqueous mixture was washed with ether(1×60 ml). The acidic solution was then basified with sodium hydroxidesolution (10 M), and the resulting oil was extracted with chloroform.The chloroform extracts were combined and dried over magnesium sulphate.Evaporation of the chloroform under reduced pressure afforded a paleyellow oil which was purified using a silica gel column and by elutionwith ethyl acetate/methanol (9:1). The product fractions were pooled andconcentrated to afford an oil which was distilled, to afford1-[3-(2,4-dichlorophenyl)prop-2-enyl]imidazole, b.p. 144°-148°/0.007mmHg.

EXAMPLE 4 Preparation of 1-[3-(2,6-Dichlorophenyl)prop-2-enyl]imidazole

1-Chloro-3-(2,6-dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was addeddropwise to a stirred solution of imidazole (3.4 g, 0.05 mol) andpotassium tert-butoxide (5.6 g, 0.05 mol) in butan-1-ol (100 ml).Following the addition, the reaction mixture was stirred and heatedunder reflux for 3.5 h.

After cooling, the reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. Hydrochloric acid (150 ml, 2 M) wasthen added to the residue, and the aqueous mixture was washed with ether(1×60 ml). The acidic solution was then basified with sodium hydroxidesolution (10 M), and the resulting oil was extracted with chloroform.The chloroform extracts were combined and dried over magnesium sulphate.Evaporation of the chloroform under reduced pressure afforded a paleyellow oil which was purified using a silica gel column and by elutionwith ethyl acetate/methanol (9:1). The product fractions were pooled andconcentrated to afford an oil which was distilled, to afford1-[3-(2,6-dichlorophenyl)prop-2-enyl]imidazole, b.p. 156°-158°/0.02mmHg.

EXAMPLE 5

By the method described in Example 1 above the following compounds wereprepared:

(a) 1-(2,4,6-trimethylbenzyl)imidazol; B.p. 104°-108°/0.005 mm Hg;

(b) 1-(3-(3,4,5-trimethoxyphenyl)prop-2-enyl)imidazole;

(c) 1-(3-(3,4-dimethoxyphenyl)prop-2-enyl)imidazole;

(d) 1-(3-(2-hydroxyphenyl)prop-2-enyl)imidazole;

(e) 1-(3-(3-bromophenyl)prop-2-enyl)imidazole;

(f) 1-(3-(4-chlorophenyl)prop-2-enyl)imidazole;

(g) 1-(3-(3,4-dimethylphenyl)prop-2-enyl)imidazole;

(h) 1-(3-(2-methoxyphenyl)prop-2-enyl)imidazole.

EXAMPLE 6 Biological Results

horse platelets were prepared from whole horse blood by differentialcentrifugation. Approximately 10⁶ platelets were homogenised in 1 ml 100mM Tris buffer pH 7.4. Various concentrations of active compound wereadded and the reaction sets incubated for 5 minutes at ambienttemperature. To each tube was added 20 nM of arachidonic acid contaning10⁶ DPM of labelled arachidonic acid and the tubes incubated for 3minutes at 37° C. in a shaking water bath. After incubation theradioactive products were extracted from the acidified aqueous phasewith ethyl acetate and after concentration resolved by thin layerchromatography on silica gel with chloroform/methanol/acetic acid/water(90:8:1:0.8) as a developing solvent. The amount of thromboxane producedwas measured by scraping the radioactive zone corresponding tothromboxane B₂ and estimating the radioactivity in a liquidscintillation counter.

The concentration of active compound to reduce the enzyme activity by50% (ED₅₀) was established. Thr results are shown in Table A.

The selectivity of the active compounds was measured in a similar mannerto that described above and the amount of PGE, PGF and PGD produced wasdetermined. The greater the selectivity, the more of theanti-aggregating prostaglandins are produced. The ED₅₀ and Selectivityresults are shown in Table A in which 0 indicates no selectivity; + lowselectivity and ++ medium selectivity.

                  TABLE A                                                         ______________________________________                                                             ED.sub.50                                                                     μg/ml                                                                            Selectivity                                        ______________________________________                                        Compound                                                                      1-(3,4-Dimethylbenzyl)imidazole                                                                      6       ++                                             1-(3-(2,4-Dichlorophenyl)prop-2-                                                                     4.1      +                                             enyl)imidazole                                                                1-(3-(2,6-Dichlorophenyl)prop-2-                                                                     1        +                                             enyl)imidazole                                                                1-(2,4,6-Trimethylbenzyl)imidazole                                                                   3.4     + +                                            EXAMPLE 7                                                                     1-(3,4-Dimethylbenzyl)imidazole (as a salt)                                                                  150 mg                                         Starch                         25 mg                                          Polyvinylpyrrolidone           2 mg                                           Magnesium stearate             3 mg                                           ______________________________________                                    

The imidazole salt is ground to a fine powder blended with the starchand then the mixture granulated with an aqueous solution of thepolyvinylpyrrolidone. The granules are sieved 1000μ, dried, sieved againand the magnesium stearate added. The mixture is then compressed intotablets.

In the same manner, tablets of1-(3-(2,4-dichlorophenyl)prop-2-enyl)imidazole and1-(3-(2,6-dichlorophenyl)prop-2-enyl)imidazole are prepared.

EXAMPLE 8

    ______________________________________                                         Tablets formulation                                                          Tablets (150 mg) of the imidazoles described in                               the preceding Example 7 are prepared in the same                              manner from the following ingredients:                                        ______________________________________                                        The imidazole compound (as a salt)                                                                      150 mg                                              Lactose                   100 mg                                              Starch                    30 mg                                               Polyvinylpyrrolidone      2 mg                                                Magnesium stearate        3 mg                                                ______________________________________                                    

In the preparation, the lactose is blended with the starch.

EXAMPLE 9

    ______________________________________                                         Tablet formulation                                                           Tablets (100 mg) of the imidazoles of Example 7                               are prepared in the same manner from the following                            ingredients:                                                                  ______________________________________                                        The Imidazole Compound (as a salt)                                                                      100 mg                                              Sodium starch glycollate  10 mg                                               Polyvinylpyrrolidone      2 mg                                                Magnesium stearate        3 mg                                                ______________________________________                                    

EXAMPLE 10

    ______________________________________                                         Tablet formulation                                                           Tablets (150 mg) of the imidazoles of Example 7                               are prepared in the same manner from the following                            ingredients, except that the starch, pregelled starch                         and imidazole compound are all blended together prior                         to granulation:                                                               ______________________________________                                        The Imidazole Compound (as a salt)                                                                      150 mg                                              Starch                    25 mg                                               Pregelled starch          5 mg                                                Magnesium stearate        3 mg                                                ______________________________________                                    

EXAMPLE 11

    ______________________________________                                        Injectable formulation                                                        ______________________________________                                        Imidazole Compound of formula (I)                                                                     15.0 g                                                Lactic Acid B.P.        q.s. to pH 3.0                                        Water for Injections B.P.                                                                             to 100.0 ml                                           ______________________________________                                    

Suspend the compound in 3/4 of the available quantity of water. Addsufficient lactic acid to dissolve the compound and to reduce the pH to3.0. Dilute to volume with Water for Injections.

Sterilise the solution by passage through a membrane filter, pore size0.22 μm.

Distribute the solution using aseptic precautions into sterilisedampoules, 1 ml per ampoule. Seal by fusion of the glass.

Each 1 ml ampoule supplies 150 mg of the imidazole compound:1(3,4-dimethylbenzyl)imidazole hydrogen fumarate.

EXAMPLE 12

    ______________________________________                                        Injectable formulation                                                        ______________________________________                                        Imidazole Compound of formula (I)                                                                     15.0 g                                                Citric Acid B.P.        q.s. to pH 3.0                                        Chlorocresol            0.1 g                                                 Water for Injections to 100.0 ml                                              ______________________________________                                    

Suspend the compound in 1/2 the final volume of Water for Injections.Add sufficient citric acid as a 10% solution in Water for Injections todissolve the compound and reduce the pH to 3.0. Dilute to volume withWater for Injections.

Sterilise the solution by passage through a membrane filter, pore size0.22 μm.

Distribute the solution with aseptic precautions into sterilised vials,25 ml per vial. Stopper with sterile rubber closures and seal with analuminium cap.

Each 1 ml of solution provides 150 mg of the compound:1-(3,4-dimethylbenzyl)imidazole hydrogen fumarate.

EXAMPLE 13 Injectable formulation

In the manner described in the preceding two Examples, injectableformulations of 1-(3-(2,4-dichlorophenyl)prop-2-enyl)imidazole and1-(3-(2,6-dichlorophenyl)prop-2-enyl)imidazole salts were prepared.

I claim:
 1. A 1-substituted-imidazole of the formula ##STR21## in whichA is selected from the group consisting of straight or branched,saturated, acyclic hydrocarbon radicals of 1, 2 or 3 carbon atoms, andstraight or branched unsaturated acyclic hydrocarbon radicals of 2 or 3carbon atoms, andR is ##STR22## wherein n is an integer which is atleast 1, and the or each Q substituent, which when n is greater than 1may be the same or different, is selected from a saturated hydrocarbongroup of from 1 to 4 carbon atoms and an unsaturated hydrocarbon groupof from 2 to 4 carbon atoms, with the provisos that(a) when A isethylidene, n is at least 2 when each Q is a saturated hydrocarbongroup; (b) when A is straight propylidene, n is at least 3 when each Qis a saturated hydrocarbon group; (c) when A is unsaturated Q may alsobe selected from alkoxy of from 1 to 4 carbon atoms; halo;trihalomethyl; hydroxy; carboxyl; a salt of such carboxyl group;carboalkoxy; carbophenoxy; carbophenalkyloxy; --NR⁶ R⁷ or --CONR⁶ R⁷ ;in which R⁶ and R⁷ may be the same or different and are hydrogen oralkyl of from 1 to 4 carbon atoms, with the further proviso that when nis 1, Q is not a saturated alkyl group nor halo; (d) when A ismethylene, ethylene or straight propylene, n is at least 3 when each Qis selected from a saturated hydrocarbon group; and (e) when A isbranched propylene, n is at least 4 when each Q is selected from asaturated hydrocarbon group;the substituted-imidazole being the freebase or a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound according to claim 1 wherein n is at least
 2. 3. A compoundaccording to claim 2 wherein one of the groups is in the 4-position ofthe benzene ring, relative to the group A.
 4. A compound according toclaim 1 wherein A is --CH₂ --.
 5. A compound according to claim 1wherein A is, in the orientation of formula (I), --CH₂ --CH═CH--.
 6. Acompound according to claim 5 wherein the group Q is selected fromalkyl, chloro or methoxy.
 7. A 1-substituted-imidazole of the formula:##STR23## in which A is selected from the group consisting of straightor branched, saturated, acyclic hydrocarbon radicals of 2 carbon atoms,and straight or branched unsaturated acyclic hydrocarbon radicals of 2or 3 carbon atoms, andR Is ##STR24## wherein n is an integer which is atleast 1, and the or each Q substituent, which when n is greater than 1may be the same or different, is selected from a saturated hydrocarbongroup of from 1 to 4 carbon atoms and an unsaturated hydrocarbon groupof from 2 to 4 carbon atoms, with the provisos that(a) when A isethylidene, n is at least 2 when each Q is a saturated hydrocarbongroup; (b) when A is unsaturated Q may also be selected from alkoxy offrom 1 to 4 carbon atoms; trihalomethyl; hydroxy; carboxyl; a salt ofsuch a carboxyl group; carboalkoxy; --NR⁶ R⁷ or --CONR⁶ R⁷ ; in which R⁶and R⁷ may be the same or different and are hydrogen or alkyl of from 1to 4 carbon atoms, with the further proviso that when n is 1, Q is not asaturated alkyl group; and(c) when A is ethylene, n is at least 3 wheneach Q is a saturated hydrocarbon group; the substituted-imidazole beingthe free base or a pharmaceutically acceptable acid addition saltthereof.
 8. A compound according to claim 7 wherein n is at least
 2. 9.A compound according to claim 8 wherein one of the groups is in the4-position of the benzene ring, relative to the group A. 10.1-(3,4-dimethylbenzyl)imidazole or a pharmaceutically acceptable acidaddition salt thereof.
 11. 1-(3,4-dimethylbenzyl)imidazole.
 12. A1-substituted-imidazole selected from1-[3-(2,4-dichlorophenyl)prop-2-enyl]imidazole,1-[3-(2,6-dichlorophenyl)prop-2-enyl]imidazole and pharmaceuticallyacceptable acid addition salts thereof.
 13. A 1-substituted imidazoleselected from 1-(2,4,6-trimethylbenzyl)imidazole,1-[3-(3,4-dimethylphenyl)prop-2-enyl]imidazole and pharmaceuticallyacceptable acid addition salts thereof.
 14. A 1-substituted-imidazoleselected from the group consistingof:1-[3-(3,4,5-trimethoxyphenyl)prop-2-enyl]imidazole;1-[3-(3,4-dimethoxyphenyl)prop-2-enyl]imidazole;1-[3-(2-hydroxyphenyl)prop-2-enyl]imidazole;1-[3-(3-bromophenyl)prop-2-enyl]imidazole;1-[3-(4-chlorophenyl)prop-2-enyl]imidazole;1-[3-(2-methoxyphenyl)prop-2-enyl]imidazole; and pharmaceuticallyacceptable acid addition salts thereof. 15.1-(2,4,6-Trimethylbenzyl)imidazole, or a pharmaceutically acceptableacid addition salt thereof.
 16. A 1-substituted-imidazole of theformula: ##STR25## in which A is a straight or branched unsaturatedacyclic hydrocarbon radical of 2 or 3 carbon atoms, andR is ##STR26##wherein n is an integer which is at least 1, and the Q substituent isselected from alkoxy of from 1 to 4 carbon atoms; trihalomethyl;hydroxy; carboxyl; a salt of such a carboxyl group; carboalkoxy; --NR⁶R⁷ or --CONR⁶ R⁷ ; in which R⁶ and R⁷ may be the same or different andare hydrogen or alkyl of from 1 to 4 carbon atoms,thesubstituted-imidazole being the free base or a pharmaceuticallyacceptable acid addition salt thereof.
 17. A compound according to claim16 wherein A is, in the orientation of formula (I), --CH₂ --CH═CH--.